Impact of Pals1 on Expression and Localization of Transporters Belonging to the Solute Carrier Family

Abstract

Pals1 is part of the evolutionary conserved Crumbs polarity complex and plays a key role in two processes, the formation of apicobasal polarity and the establishment of cell-cell contacts. In the human kidney, up to 1.5 million nephrons control blood filtration, as well as resorption and recycling of inorganic and organic ions, sugars, amino acids, peptides, vitamins, water and further metabolites of endogenous and exogenous origin. All nephron segments consist of polarized cells and express high levels of Pals1. Mice that are functionally haploid for Pals1 develop a lethal phenotype, accompanied by heavy proteinuria and the formation of renal cysts. However, on a cellular level, it is still unclear if reduced cell polarization, incomplete cell-cell contact formation, or an altered Pals1-dependent gene expression accounts for the renal phenotype. To address this, we analyzed the transcriptomes of Pals1-haploinsufficient kidneys and the littermate controls by gene set enrichment analysis. Our data elucidated a direct correlation between TGFβ pathway activation and the downregulation of more than 100 members of the solute carrier (SLC) gene family. Surprisingly, Pals1-depleted nephrons keep the SLC’s segment-specific expression and subcellular distribution, demonstrating that the phenotype is not mainly due to dysfunctional apicobasal cell polarization of renal epithelia. Our data may provide first hints that SLCs may act as modulating factors for renal cyst formation.

PALS1 is a key regulator of the lateral distribution of tight junction proteins in renal epithelial cells

“…In other words: minor changes in TJ formation dynamics, maintenance or in the distribution of central TJ proteins may have very severe consequences in vivo. The dysfunctional lateral distribution of TJ proteins in PALS1 KO and KD cells and the strong phenotype of Pals1 haplo-insufficient mice in which already a partial Pals1 depletion caused severe defects -although the well-defined apicobasal distribution of important proteins is in principle preserved -supports this assumption [11,12]. Further research will be necessary to clarify to what extent even minor modifications of the "tightness of TJs" contribute to renal pathomechanisms.…”

“…For instance, mice lacking CRB3 or LIN7 develop cysts in the renal tubules of the kidneys [8][9][10]. In addition, heterozygous PALS1 knockout mice with a reduced PALS1 expression in all nephron epithelia [11] developed proteinuria and formed numerous cysts leading to death within the first two months after birth [11,12]. Remarkably, in case of PALS1 the loss of only one allele was sufficient to cause this phenotype, indicating a crucial and dose-dependent function of PALS1 in renal epithelial cells [11].…”